Type 1 diabetes mellitus (T1D) in humans is associated with several disorders of skeletal health, including decreased bone mineral density (BMD) and an increased risk for osteoporosis and fragility fractures. These features are the primary clinical characteristics of diabetic bone disease (DBD). Evidence suggests that DBD occurs early in the progression of T1D, involves impaired bone formation, includes micro-architectural abnormalities and poor bone quality, and eventually may lead to abnormal bone turnover. Despite what is known clinically, the pathogenic mechanisms behind these findings are not well understood. Translational studies in rodent models of T1D DBD have begun to unravel how a compromised skeleton can arise in the diabetic state, what are the mechanisms involved in the process, and what therapeutics might be most appropriate to prevent or treat DBD. Studies in mouse models, supported by human studies, suggest that impairment in insulin and insulin-like growth factor-I (IGF-I) production and action may be central events in promoting DBD. Recent data from our laboratory and others have demonstrated that: 1) severe deficits in bone formation occur in the context of insulin- deficiency in mouse models of T1D; 2) insulin therapy can improve both cancellous and cortical bone, thereby increasing fracture resistance; 3) normalization of systemic insulin levels stimulates bone formation through RUNX2 and RUNX2 target genes in diabetic animals; and 4) insulin and IGF-I may signal via similar down-stream pathways to promote osteoblastogenesis. Nonetheless, overlap and compensation between each ligand for the other has not been established in the diabetic state, nor have the downstream mediators or critical signaling pathways been identified. To clarify the mechanisms by which insulin and/or IGF-I modulate osteogenesis and to understand how deficiencies of impaired signaling of each may contribute to DBD, we will carry out studies to 1) determine how insulin and IGF-1 deficiencies contribute to DBD and 2) how each may perform overlapping and independent effects through specific downstream signaling pathways to prevent diabetic bone disease and/or reverse DBD.